rs794728470

chr7-150947367-A-ACGTCGCCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000238.4(KCNH2):c.3112_3113insGGGCGACG(p.Val1038GlyfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V1038V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0210

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-150947367-A-ACGTCGCCC is Pathogenic according to our data. Variant chr7-150947367-A-ACGTCGCCC is described in ClinVar as [Pathogenic]. Clinvar id is 200705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.3112_3113insGGGCGACG	p.Val1038GlyfsTer22	frameshift_variant	13/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.3112_3113insGGGCGACG	p.Val1038GlyfsTer22	frameshift_variant	13/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.2092_2093insGGGCGACG	p.Val698GlyfsTer22	frameshift_variant	9/11	1
KCNH2	ENST00000684241.1	n.3945_3946insGGGCGACG		non_coding_transcript_exon_variant	11/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 21, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 200705). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val1038Glyfs*22) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2012

c.3105_3112dupGGGCGACG: p.Val1038GlyfsX22 (V1038GfsX22) in exon 13 of the KCNH2 (aka HERG) gene (NM_000238.2). The normal sequence with the bases that are inserted in braces is: GACG{GGGCGACG}TGGA.Although the c.3105_3112dupGGGCGACG mutation in the KCNH2 gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Valine 1038, changing it to a Glycine, and creating a premature stop codon at position 22 of the new reading frame, denoted p.Val1038GlyfsX22. This mutation is expected to result in an abnormal, truncated protein product. Other frameshift mutations in the KCNH2 gene have been reported in association with LQTS. In summary, c.3105_3112dupGGGCGACG in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794728470; hg19: chr7-150644455;